This proposal outlines chemical syntheses of three macrocylic (large-ring) natural products all of which contain a C2-axis of symmetry. A major focus of the work will be to develop a variety of new strategies for controlling the selectivity between macrocyclization (ring-forming) reactions and the competitive and deleterious repetitive intermolecular coupling reactions which leads, ultimately, to polymers. Although dimeric macrocyclic dilactones are known and have been synthesized, there currently exists no demonstrated strategy for synthesis of compounds like the targets of this study. The precursors to ring closure will in all cases be chiral molecules which are bifunctional. That is, each incorporates a pair of reactive centers which will spontaneously react with one another when deprotected and/or exposed to the proper catalyst and/or mild reaction conditions. One of the major strategies for controlling the cyclization event relies on the incorporation of structural elements which serve in effect to reduce the number of degrees of freedom available in the precursor. This, in turn, should reduce the entropy of activation for the ring-closure. Another, new strategy involves the tethering of two bifunctional molecules to one another prior to effecting the cyclization. These studies will significantly expand the limited scope of existing methodology for the creation of macrocylic natural products--a class well-known to encompass wide ranges of structural types and biological properties. The specific molecules whose syntheses will be addressed here are: Cylindrocyclophane A (I): This new molecule represents the first example of a naturally occurring [m,n]-paracyclophane. The proposed synthetic studies will provide many opportunities for the rational design and evaluation of removable tether molecules to control both the cyclization chemistry as well as the subsequent establishment of the remaining stereochemical (three-dimensional) features of the structure. This compound shows antitumor activity against at least two cell lines. Petrosin (II) and Xestospongin A (III): The structures of both of these alkaloids include a pair of bicyclic, nitrogen-containing heterocyclic units which are embedded within the macrocyclic ring of their pentacyclic nuclei. The former, along with two close structural relatives, was identified because of its powerful ichthyotoxic properties. The latter, again along with three structural relatives, is a vasodilative compound and induces in vivo relaxation of blood vessels. In the proposed syntheses of each of these alkaloids, the relative stereochemistry in the heterocyclic portion will be controlled by thermodynamically driven equilibrations of all but one of the stereogenic centers in each heterocyclic component. Variation of the nature and extent of rigidity in the arms linking the reactive ends of each monomeric precursor and the resultant impact of these changes on the cyclodimerization event will be a major focus of these studies.